Benzopyrane derivatives

ABSTRACT

New benzopyrane derivatives of the general formula ##STR1## in which R is free, esterified or amidated carboxyl, Ph is 1,2-phenylene which contains the group R--CO--NR 3  -- and is otherwise unsubstituted or is substituted, X is a group of the formula --CO--CR 1  ═CR 2  --, in which R 1  and R 2  independently of one another are hydrogen, acyl or a substituted or unsubstituted hydrocarbon radical or a hetero-analogue thereof, or conjointly are 3-membered to 5-membered lower alkylene, and R 2  can also be free or etherified hydroxyl or hydroxyl etherified by an organic carboxylic acid, and R 3  is hydrogen or lower alkyl, are useful as anti-allergic agents.

This is a divisional of application Ser. No. 826,224, filed on Aug. 19,1977, now U.S. Pat. No. 4,205,082, issued May 27, 1980.

The invention relates to a process for the preparation of novelbenzopyrane derivatives of the general formula ##STR2## in which R isfree, esterified or amidated carboxyl, Ph is 1,2-phenylene whichcontains the group R--CO--NR₃ -- and is otherwise unsubstituted or issubstituted, X is a group of the formula --CO--CR₁ ═CR₂ --, in which R₁and R₂ independently of one another are hydrogen, acyl or a substitutedor unsubstituted hydrocarbon radical or a hetero-analogue thereof, orconjointly are 3-membered to 5-membered lower alkylene, and R₂ can alsobe free or etherified hydroxyl or hydroxyl etherified by an organiccarboxylic acid, and R₃ is hydrogen or lower alkyl, in the free form orin the form of a salt, the novel compounds themselves, pharmaceuticalformulations containing these compounds and the use of suchformulations.

Esterified carboxyl is, for example, carboxyl esterified by asubstituted or unsubstituted alcohol of aliphatic or aromatic character.

An alcohol of aliphatic character is an alcohol in which the C atombonded to the hydroxyl group is not a member of an aromatic system, forexample an aliphatic alcohol which is unsubstituted or substituted bysubstituted or unsubstituted aryl or hetero-aryl, for examplesubstituted or unsubstituted phenyl or pyridyl, a possible alcohol ofthis type being, for example, a lower alkanol, or is a cycloaliphaticalcohol, for example a 5-membered to 8-membered cycloalkanol. Exampleswhich may be mentioned of carboxyl esterified by a substituted orunsubstituted alcohol of aliphatic character are: lower alkoxy-carbonyl,for example methoxy-, ethoxy-, propoxy-, isopropoxy- andbutoxy-carbonyl, phenyl-lower alkoxy-carbonyl, in particular α- andβ-phenyl-lower alkoxy-carbonyl, which is unsubstituted or substituted inthe phenyl part, possible substituted or unsubstituted phenyl andpossible lower alkoxy being, in particular, those mentioned below, forexample benzyloxycarbonyl and α- and β-phenethoxycarbonyl, and5-membered to 8-membered cycloalkoxycarbonyl, for examplecyclopentyloxy-, cyclohexyloxy- and cycloheptyloxy-carbonyl.

An alcohol of aromatic character is an alcohol in which the C atombonded to the hydroxyl group is a member of a carbocyclic orheterocyclic aromatic system, for example a phenol which isunsubstituted or substituted in the phenyl part or a hydroxypyridinewhich is substituted by lower alkyl, such as methyl, or lower alkoxy,such as methoxy. Examples which may be mentioned of carboxyl esterifiedby a substituted or unsubstituted alcohol of aromatic character are:phenoxy-, tolyloxy-, anisyloxy- and chlorophenoxy-carbonyl and also 2-,3- and 4-pyridyloxycarbonyl.

Amidated carboxyl contains, as the amino group, for example a free aminogroup or an amino group which is substituted by at least one substitutedor unsubstituted hydrocarbon radical of aliphatic character, or ahetero-analogue thereof, or a substituted or unsubstituted aryl radical.

In a substituted or unsubstituted hydrocarbon radical of aliphaticcharacter, or a hetero-analogue thereof, the free valency emanates froma non-aromatic C atom. A radical of this type is, for example, loweralkyl or lower alkenyl, which can be substituted by substituted orunsubstituted phenyl or naphthyl, or, for example, 5-membered to8-membered cycloalkyl, such as cyclohexyl, or unsubstituted or loweralkylated, for example methylated, 4-membered to 7-membered alkylene, ora monooxa-, -aza- or -thia-analogue thereof, for example tetramethyleneor pentamethylene or 3-oxa-, 3-aza- or 3-thia-pentamethylene. Exampleswhich may be mentioned of carbamyl substituted by at least one suchradical are: mono- or di-lower alkyl-carbamyl, such as N-methyl- andN,N-diethyl-carbamyl, phenyl-lower alkyl-carbamyl which in the phenylpart is unsubstituted or substituted as indicated below, such asN-benzyl- or N-(1- or 2-phenethyl)-carbamyl, or pyrrolidinocarbonyl,piperidinocarbonyl, morpholinocarbonyl, thiomorphininocarbonyl,piperazinocarbonyl or 4-lower alkyl-piperizinocarbonyl, for example4-methyl-piperazinocarbonyl.

A substituted or unsubstituted aryl radical is, for example, substitutedor unsubstituted naphthyl, or phenyl which is unsubstituted orsubstituted as indicated below and/or substituted on two adjacent ringatoms by a group --OX--, which has the meaning defined. Examples whichmay be mentioned of carbamyl groups substituted by a radical of thistype are, for example, N-phenyl-, N-tolyl-, N-anisyl-, N-chlorophenyl-and N-naphthyl-carbamyl as well as groups of the formula ##STR3##

1,2-Phenylene Ph which contains the group R--CO--NR₃ -- can alsocontain, in addition to this group, at least one, for example one ortwo, further substituents, examples of possible substituents being loweralkyl, such as those mentioned below, for example methyl, lower alkoxy,such as those mentioned below, for example methoxy, halogens, such asthose mentioned below, for example chlorine, and trifluoromethyl.

Acyl is, for example, acyl derived from an organic carboxylic acid orfrom free, partially esterified or amidated carbonic acid.

Acyl derived from a carboxylic acid is, for example, lower alkanoyl orsubstituted or unsubstituted benzoyl, for example, acetyl, propionyl,butyryl or benzoyl.

Acyl derived from free, partially esterified or amidated carbonic acidis, for example, free, esterified or amidated carboxyl, such as freecarboxyl or carboxyl esterified or amidated as indicated above, forexample carboxyl, methoxy- or ethoxy-carbonyl or carbamyl.

Free or etherified hydroxyl is, for example, free hydroxyl or hydroxyletherified by a lower alkanol or by a substituted or unsubstitutedphenol, i.e. hydroxyl, lower alkoxy or substituted or unsubstitutedphenoxy, for example hydroxyl, methoxy, ethoxy or phenoxy.

Free hydroxyl or hydroxyl esterified by carboxylic acid is, for example,free hydroxyl or hydroxy esterified by a lower alkanecarboxylic acid orby a substituted or unsubstituted benzoic acid, i.e. hydroxyl, loweralkanoyloxy or substituted or unsubstituted benzoyloxy, especiallyacetoxy, propionyloxy or benzoyloxy.

A substituted or unsubstituted hydrocarbon radical or a hetero-analoguethereof is, for example, a substituted or unsubstituted hydrocarbonradical of aliphatic character or a substituted or unsubstitutedaromatic hydrocarbon radical or a hetero-analogue thereof.

3-membered to 5-membered lower alkylene can be straight-chain orbranched and is, for example, 1,3-propylene, 1,4-butylene, 1,5-pentyleneor 2- or 3-methyl-1,4-butylene.

In a substituted or unsubstituted hydrocarbon radical of aliphaticcharacter the free valency emanates from a nonaromatic C atom. A radicalof this type is, for example, an aliphatic hydrocarbon radical which isunsubstituted or substituted by substituted or unsubstituted phenyl, forexample a lower alkyl radical, or a cycloaliphatic hydrocarbon radical,such as adamantyl or monocyclic 5-membered to 8-membered cycloalkyl orcycloalkenyl, for example 1-cycloalkenyl. Examples of such radicalswhich may be mentioned in particular are: methyl, ethyl, isopropyl andbutyls, benzyl and methyl-, methoxy- and chloro-benzyls, cyclopentyl,cyclohexyl, 1-cyclohexenyl, cycloheptyl and 1-cycloheptenyl.

A substituted or unsubstituted aromatic hydrocarbon radical or ahetero-analogue thereof contains, for example 5 or 6 ring members and upto 2 hetero-atoms, such as a nitrogen, oxygen or sulphur atom, and is,for example, substituted or unsubstituted phenyl, such as one of thosebelow, or a 5-membered or 6-membered hetero-aryl radical containing anitrogen, oxygen or sulphur atom, such as, for example, one of thosebelow. Examples are, in particular, phenyl or pyridyl which areunsubstituted or substituted by methyl, methoxy or chlorine.

The following applies in the preceding and following text:

Substituted or unsubstituted phenyl and naphthyl and also phenyl insubstituted or unsubstituted benzoyl, benzoyloxy and aromatic alcoholsis, for example, phenyl or naphthyl which is unsubstituted ormonosubstituted or polysubstituted, for example monosubstituted ordisubstituted, possible substituents being, in particular, lower alkyl,lower alkoxy or halogens, for example those mentioned below, hydroxyland also trifluoromethyl, such as phenyl, naphthyl, o-, m- or p-tolyl,o-, m- or p-anisyl, o- or p-chlorophenyl or 2,4-, 3,5- or2,6-dichlorophenyl.

Substituted or unsubstituted hetero-aryl, and substituted orunsubstituted hetero-aryl in hetero-aromatic alcohols, preferably has 5or 6 ring members and contains, as the hetero-atom or hetero-atoms up totwo nitrogen, oxygen and/or sulphur atoms and is, for example,unsubstituted or monosubstituted or polysubstituted pyridyl, thienyl orfuryl, possible substituents being lower alkyl, lower alkoxy andhalogens, in particular, in each case, those mentioned below, such as2-, 3- or 4-pyridyl, 6-methyl-2-pyridyl, 6-methoxy-2-pyridyl or 2- or3-thienyl.

Lower alkyl contains, for example, up to 7 and in particlar up to 4 Catoms and can be straight-chain or branched and bonded in any desiredposition, such as methyl, ethyl, propyl or n-butyl or also isopropyl,sec.-butyl or isobutyl.

Lower alkoxy, and also lower alkoxy in lower alkoxy-carbonyl, contains,for example, up to 7 and in particular up to 4 C atoms and can bestraight-chain or branched and bonded in any desired position, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy or amyloxy.

Lower alkanoyl, and also lower alkanoyl in lower alkanoyloxy, contains,for example, up to 7 and in particular up to 4 C atoms and can bestraight-chain or branched, such as acetyl, propionyl, butyryl orisobutyryl.

Halogen is, for example, halogen having an atomic number of up to andincluding 35, such as fluorine, chlorine or bromine.

Salts of compounds of the general formula (I), in which R, R₁ and/or R₂is carboxyl, are salts with bases, in particular corresponding saltswhich can be used pharmaceutically, such as alkali metal salts oralkaline earth metal salts, for example sodium salts, potassium salts,magnesium salts or calcium salts, and also ammonium salts with ammoniaor amines, such as lower alkyl-amines or hydroxy-lower alkyl-amines, forexample trimethylamine, triethylamine or di- ortri-(2-hydroxyethyl)-amine.

The novel compounds show valuable pharmacological properties. Inparticular, they show anti-allergic actions, which can be demonstrated,for example, on rats in doses of about 1 to about 100 mg/kg on oraladministration in the passive cutaneous anaphylaxis test (PCA reaction),which is carried out analogously to the method described by Goose andBlair, Immunology, Volume 16, page 749 (1969), passive cutaneousanaphylaxis being produced by the procedure described by Ovary, Progr.Allergy, Volume 5, page 459 (1958). They also effect inhibition of theimmunologically induced release of hystamine, for example from theperitoneal cells of rats infested with Nippostrongylus brasiliensis, invitro, (cf. Dukor et al., Intern. Arch. Allergy (1976), to bepublished). Furthermore, they are highly active in variousbronchoconstrictions induced artificially, as can be shown, for example,in the dosage range of about 1 to about 3 mg/kg, administeredintraveneously, with the aid of the bronchoconstriction produced by IgEantibodies in rats and in the dosage range of from about 1 mg/kg,administered intraveneously, with the aid of the bronchoconstrictioninduced by IgG antibodies in guinea pigs. The compounds of the presentinvention are useful as inhibitors of allergic reactions, for example inthe treatment and prophylaxis of allergic diseases, such as asthma,including both extrinsic and intrinsic asthma, or other allergicdiseases, such as hayfever, conjunctivitis, urticaria and eczema.

The invention relates, in particular, to compounds of the generalformula I in which R is carboxyl, carboxy esterified by an alcohol ofaliphatic or aromatic character or carbamyl which is unsubstituted orsubstituted by at least one substituted or unsubstituted hydrocarbonradical of aliphatic character, or a hetero-analogue thereof, or by asubstituted or unsubstituted aryl radical, Ph is 1,2-phenylene whichcontains the group R--CO--NR₃ -- and is otherwise unsubstituted or issubstituted, X is a group --CO--CR₁ ═CR₂ --, in which R₁ and R₂independently of one another are hydrogen, lower alkanoyl, benzoyl, freecarboxyl, carboxyl esterified or amidated as indicated above for R or asubstituted or unsubstituted hydrocarbon radical of aliphatic characteror an aromatic hydrocarbon radical, or a hetero-analogue thereof, orconjointly are 1,3-, 1,4- or 1,5-lower alkylene, and R₂ can also be freehydroxyl or hydroxyl etherified by a lower alkanol or esterified by alower alkanecarboxylic acid, and R₃ is hydrogen or lower alkyl, possiblesubstituents of aromatic and heteroaromatic groups being, in each case,in particular lower alkyl, such as methyl, lower alkoxy, such asmethoxy, halogen, such as chlorine, hydroxyl and trifluoromethyl, in thefree form or in the form of a salt.

The invention relates, in particular, to compounds of the generalformula I in which R is carboxyl, carboxyl esterified by a lower alkanolwhich is unsubstituted or substituted by substituted or unsubstitutedphenyl or carboxyl esterified by a substituted or unsubstituted phenol,or carbamyl which is unsubstituted, monosubstituted by lower alkyl,substituted or unsubstituted phenyl-lower alkyl or substituted orunsubstituted phenyl, for example a group ##STR4## in which Ph and X areas defined below, or disubstituted by lower alkyl or by lower alkyleneor a hetero-analogue thereof, Ph is 1,2-phenylene which contains thegroup R--CO--NR₃ -- and is otherwise unsubstituted or is substituted, Xis a group --CO--CR₁ ═CR₂ --, in which R₁ and R₂ independently of oneanother are hydrogen, lower alkanoyl, such as acetyl, free carboxyl orcarboxyl esterified by a lower alkanol, such as methanol, lower alkylwhich is unsubstituted or substituted by phenyl, which, in turn, can besubstituted, or substituted or unsubstituted phenyl or 5-membered to6-membered heteroaryl containing a nitrogen, oxygen or sulphur atom, orconjointly are tri-, tetra- or penta-methylene and R₂ can also be freehydroxyl or hydroxyl etherified by a lower alkanol, such as methanol, oresterified by a lower alkanecarboxylic acid, such as acetic acid, and R₃is hydrogen or lower alkyl, possible substituents of phenyl, phenol,1,2-phenylene Ph and heteroaryl being lower alkyl, such as methyl, loweralkoxy, such as methoxy, halogen, such as chlorine, hydroxyl andtrifluoromethyl, in the free form or in the form of a salt.

The invention relates especially, on the one hand, to compounds of thegeneral formula Ia ##STR5## and, on the other hand, to compounds of thegeneral formula Ib ##STR6## in which, in each case, R_(o) is carboxyl,lower alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, phenyl-loweralkoxy-carbonyl which in the phenyl part is unsubstituted or substitutedas indicated below, such as benzyloxycarbonyl, or free carbamyl,carbamyl monosubstituted or disubstituted by lower alkyl, such as methylor ethyl, or carbamyl disubstituted by tetra- or penta-methylene or3-oxa-, 3-aza- or 3-thia-pentametylene, Ph' is 1,2-phenylene whichcontains the group R_(o) --CO--NH-- and, in addition, is otherwiseunsubstituted or is substituted as indicated below, R₁ ' and R₂ 'conjointly are tri-, tetra- or penta-methylene, or R₁ ' is hydrogen,lower alkanoyl, such as acetyl, carboxyl, lower alkoxy-carbonyl, such asmethoxy- or ethoxy-carbonyl, lower alkyl, such as methyl, or phenyl orpyridyl which are unsubstituted or substituted as indicated below, andR₂ ' has one of the meanings given for R₁ ' or is hydroxyl, loweralkoxy, such as methoxy, or lower alkanoyloxy, such as acetoxy, possiblesubstituents of substituted phenyllower alkoxy-carbonyl R' oradditionally substituted 1,2-phenylene Ph' and of substituted phenyl andpyridyl R₁ ' and/or R₂ ' being, lower alkyl, such as methyl, loweralkoxy, such as methoxy, halogen, such as chlorine, hydroxyl andtrifluoromethyl, in each case in the free form or in the form of a salt.

The invention relates primarily on the one hand to compounds of thegeneral formula Ia in which R_(o) is carboxyl or lower alkoxy-carbonylhaving up to 5 C atoms, such as methoxy- or ethoxy-carbonyl, Ph' is1,2-phenylene which contains the group R_(o) --CO--NH, for examplebonded in the 4-position or 5-position, and is otherwise unsubstitutedor substituted in one of the free positions by lower alkyl or loweralkoxy having, in each case, up to 4 C atoms, such as methyl or methoxy,or hydroxyl or halogen, such as chlorine, R₁ ' is hydrogen or loweralkyl or lower alkanoyl, having, in each case, up to 4 C atoms, such asmethyl or acetyl, or is phenyl or pyridyl and R₂ ' has one of themeanings given for R₁ ' or is hydroxyl or lower alkoxy having up to 4 Catoms, such as methoxy, and, on the other hand, to compounds of thegeneral formula Ib in which R_(o) and Ph' are as defined above and R₁ 'and R₂ ' independently of one another are hydrogen, lower alkyl havingup to 4 C atoms, such as methyl, or phenyl, in each case in the freeform or in the form of a salt.

The invention relates very particularly to compounds of the formula Ic##STR7## in which one of the radicals R₆ and R₇ is a group of theformula R_(o) '--CO--NH, in which R_(o) ' is carboxyl or, lesspreferentially, lower alkoxy-carbonyl having up to 5 C atoms, such asmethoxy- or ethoxy-carbonyl, and the other is hydrogen and R₃ and R₄independently of one another are hydrogen or lower alkyl having up to 4C atoms, such as methyl, in the free form or in the form of a salt.

The novel compounds can be prepared according to processes which areknown per se.

A preferred procedure comprises, for example, the reaction of a compoundof the general formula II ##STR8## in which Ph, R₃ and X have thedefined meanings, or a salt thereof, with a functionally modified oxalicacid of the formula R--Y in which Y is an esterified carboxyl group or acarboxyl group which has been converted to an anhydride with ahydrogenhalide acid and, if desired, the conversion of a compound thusobtained into another compound of the general formula (I) and/or theconversion of a resulting salt-forming compound into a salt or of aresulting salt into the free compound.

Salts of compounds of the formula II are, for example, hydrohalides,such as hydrochlorides, thereof and also salts with oxalic acid ormonoester or monoamide thereof.

Functional derivatives of oxalic acid are for example symmetrical oxalicacid diesters, such as di-lower alkyl esters, and esterifiedhalogenooxalic acids of the formula R-CO-Hal, in which Hal is chlorineor bromine.

The reaction can be carried out in a customary manner, especially in themanner known from the literature for analogous reactions, if necessaryin the presence of a condensing agent, for example in the presence of abasic condensing agent, such as a tertiary organic nitrogen base, forexample triethylamine or pyridine, or of an alkali metal hydroxide oralkali metal carbonate, for example of sodium hydroxide or potassiumhydroxide, in the case of the reaction with an ester-halide of oxalicacid, and/or in an inert solvent, preferably an inert polar solvent,such as a N,N-dialkylamide, for example in N,N-dimethylformamide orN,N-dimethylacetamide.

With this reaction, oxalic acid ester-amides and/or symmetrical oxalicacid diamides of the general formula (I) can be obtained, in accordancewith the particular molar ratios and concentration ratios of the oxalicacid component used and on the reaction conditions. If, for example, theequimolar amount of an oxalic acid ester-halide is added to a solutionof the amine component of the general formula (II) and a tertiaryorganic nitrogen base at a moderate reaction temperature, for example at0° to 80° and preferably 15° to 50°, or if the equimolar amount of anoxalic acid diester is initially introduced and the amine component isadded, oxalic acid ester-amides of the general formula (I) arepreferentially obtained. Conversely, when an excess of the aminecomponent is used under more drastic reaction conditions and/or theamine component is initially introduced, symmetrical oxamides of thegeneral formula (I) are preferentially obtained from the reaction withoxalic acid diesters.

The novel compounds can also be prepared by converting in a compound ofthe formula ##STR9## a radical R' of the formula X₁ --NR₃ -- in which X₁denotes a halogenooxalyl group, into a group of the formula R--CO--NR₃-- by solvolysis, or a radical R' of the formula X₂ --NR₃ -- in which X₂denotes a glyoxyloyl group or an optionally etherfied glycoloyl group,into an optionally esterified oxaloamino group R--CO--NR₃ -- byoxidation and, if desired, converting a compound which is thusobtainable into another compound of the formula I and/or converting aresulting salt into the free compound or into another salt or convertinga resulting salt-forming compound into a salt.

In this context, halogenooxalyl X₁ is especially chlorooxalyl andsolvolysis means hydrolysis, alcoholysis (reaction with the alcoholcorresponding to the desired esterified carboxyl group R-) and/orammono- or aminolysis (reaction with ammonia or an amine correspondingto the desired amidated carboxyl group).

Thus, for example, a halogenooxalyl group X₁ can be converted into thefree oxalo group by hydrolysis, for example in the presence of an acidor basic agent, such as of a mineral acid, for example hydrochloricacid, or of an alkali metal hydroxide, for example sodium hydroxidesolution or potassium hydroxide solution, the reaction preferably beingcarried out under acid conditions and/or in the presence of an oxidisingagent, for example hydrogen peroxide, in the case of the hydrolysis ofcyanocarbonyl groups or of thiooxalo groups of the oxalo group. Thereaction is, if necessary, carried out in a polar solvent, such as alower alkanol, ketone or ether, for example in ethanol, acetone ordioxane, and/or with cooling or warming, for example at about 0° C. toabout 100° C.

A halogenooxalyl group X₁ can also be converted into esterified oxalogroups by conventional alcoholysis, i.e. by reaction with thecorresponding alcohol. The reaction is advantageously carried out in thepresence of a basic condensing agent, for example of pyridine ortriethylamine. In an analogous manner, a halogenooxalyl group X₁ can beconverted into an amidated oxalo group R--C(═O)-- by ammonolysis oraminolysis, i.e. by reaction with ammonia or a corresponding primary orsecondary amine, preferably in the presence of a basic condensing agent,for example of sodium hydroxide, pyridine or triethylamine.

A glyoxyloyl group X₂ which can be hydrated can advantageously be formedin situ in the course of the oxidation reaction, for example from theacyl group of an aliphatic or araliphatic carboxylic acid which can beα,β-unsaturated or α,β-dihydroxylated, a glycoloyl group, which can beesterified on the hydroxyl group, or the glycyl group, or can be setfree from one of its functional derivatives, for example from one of itsacetals or imines. Acyl groups of carboxylic acids which can beα,β-unsaturated or α,β-dihydroxylated are, for example, alkanoyl groups,such as lower alkanoyl, for example acetyl, acyl groups ofα,β-unsaturated aliphatic monocarboxylic or dicarboxylic acids, forexample acryloyl, crotonyl or the acyl group of free or functionallymodified fumaric acid or maleic acid, acyl groups of α,β-unsaturatedaraliphatic carboxylic acids, for example substituted or unsubstitutedcinnamoyl, or acyl groups of aliphatic α,β-dihydroxydicarboxylic acids,such as of tartaric acid, or monofunctional carboxy derivatives, such asesters or amides, thereof. Esterified glycoloyl groups are, for example,glycoloyl groups esterified on the hydroxyl group by a mineral acid,such as a hydrogen halide acid, for example by hydrochloric acid orhydrobromic acid, or by a carboxylic acid, for example by acetic acid orsubstituted or unsubstituted benzoic acid. Acetalised glyoxyloyl groupsare, for example, glyoxyloyl groups acetalised by lower alkanols or alower alkane-diol, such as dimethoxy-, diethoxy- orethylenedioxy-acetyl. Imines of glyoxyloyl groups are, for example,substituted or unsubstituted N-benzylimines orN-(2-benzothiazolyl)-imines thereof or imines with3,4-di-tert.-butyl-o-quinone.

The oxidation can be carried out in a customary manner by reaction witha suitable oxidising agent. Suitable oxidising agents are, especially,oxidising heavy metal compounds, such as silver compounds, for examplesilver nitrate or silver picolinate, oxy-acids of heavy metals, forexample of manganese-IV, manganese-VII, chromium-VI and iron-VI, or ofhalogens, or their anhydrides or salts, such as chromic acid, chromiumdioxide, potassium dichromate, potassium permanganate, manganesedioxide, potassium ferrate, sodium iodate, sodium periodate or leadtetraacetate. The reaction with these oxidising agents is effected in acustomary manner, for example in an inert solvent, such as acetone,acetic acid, pyridine or water, or a mixture, preferably an aqueousmixture, of inert solvents, at normal temperature or, if necessary, withcooling or warming, for example at about 0° C. to about 100° C. Theoxidation of free or etherified glycoloyl groups to free or esterifiedoxalo groups is, for example, advantageously carried out with potassiumpermanganate in aqueous pyridine or acetone at room temperature.Acetalised glyoxyloyl groups and imino-acetyl groups are preferablyoxidised under acid conditions, for example with potassium dichromate insulphuric acid. Acyl groups of α,β-dihydroxylated aliphatic carboxylicacids, such as the acyl radical of tartaric acid, are advantageouslyoxidised with periodic acid, whilst potassium ferrate in an alkalinemedium, for example at pH=10 to 13, for example 11.5, or organic silversalts, such as silver picolinate, are preferably used for the oxidationof the glycyl group. Groups of the formula R--CH═N-- are preferablyoxidised with an organic per-acid, for example with peracetic acid orm-chloroperbenzoic acid, in an inert solvent, for example methylenechloride, chloroform or benzene.

A compound of the general formula I which is obtainable according to theinvention can be converted into another compound of the general formulaI in a manner which is known per se.

Thus, for example, a free carboxyl group R can be esterified to anesterified carboxyl group R in a customary manner, for example bytreatment with a diazo-lower alkane, which is unsubstituted orsubstituted by substituted or unsubstituted aryl or hetero-aryl, or atri-lower alkyl-oxonium, tri-lower alkyl-carboxonium or di-loweralkyl-carbonium salt, such as hexachloroantimonate orhexafluorophosphate, or, in particular, by reaction with thecorresponding alcohol or a reactive derivative, such as a carboxylicacid ester, phosphorous acid ester, sulphurous acid ester or carbonicacid ester, for example a lower alkane-carboxylic acid ester, atri-lower alkyl phosphite, di-lower alkyl sulphite or the pyrocarbonate,or a mineral acid ester or sulphonic acid ester, for example thehydrochloric acid ester or hydrobromic acid ester or sulphuric acidester, benzenesulphonic acid ester, toluenesulphonic acid ester ormethanesulphonic acid ester, of the corresponding alcohol, or with anolefin derived therefrom.

The reaction with the corresponding alcohol itself can advantageously becarried out in the presence of an acid catalyst, such as a proton-acid,for example hydrochloric acid or hydrobromic acid, sulphuric acid,phosphoric acid, boric acid, benzenesulphonic acid and/ortoluenesulphonic acid, or a Lewis acid, for example borontrifluoride-etherate, in an inert solvent, especially an excess of thealcohol employed, and, if necessary, in the presence of a water-bindingagent and/or with removal of the water of reaction by distillation, forexample as an azeotrope, and/or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol canbe carried out in a customary manner and, when starting from acarboxylic acid ester, phosphorous acid ester, sulphurous acid ester orcarbonic acid ester, can be carried out, for example, in the presence ofan acid catalyst, such as one of those mentioned above, in an inertsolvent, such as an aromatic hydrocarbon, for example in benzene ortoluene, or in an excess of the alcohol derivative employed or of thecorresponding alcohol, the water of reaction being distilled off ifnecessary, for example as an azeotrope. Starting from a mineral acidester or sulphonic acid ester, the acid to be esterified isadvantageously employed in the form of a salt, for example the sodium orpotassium salt, and the reaction is carried out, if necessary, in thepresence of a basic condensing agent, such as an inorganic base, forexample sodium hydroxide or sodium carbonate, potassium hydroxide orpotassium carbonate or calcium hydroxide or calcium carbonate, or of atertiary organic nitrogen base, for example triethylamine or pyridine,and/or in an inert solvent, such as one of the above tertiary nitrogenbases or a polar solvent, for example in dimethylformamide, and/or atelevated temperature.

The reaction with an olefin can be carried out, for example, in thepresence of an acid catalyst, for example a Lewis acid, for exampleboron trifluoride, or a sulphonic acid, for example p-toluenesulphonicacid, or, in particular, of a basic catalyst, for example sodiumhydroxide or potassium hydroxide, advantageously in an inert solvent,such as an ether, for example in diethyl ether or tetrahydrofurane.

A free carboxyl group R can, furthermore, be converted into an amidatedcarboxyl group R by reaction with ammonia or an amine containing atleast one hydrogen atom, in the customary manner, with dehydration ofthe ammonium salt formed as an intermediate, for example by azeotropicdistillation with benzene or toluene or by dry heating.

The conversions, described above, of free carboxyl groups R intoesterified or amidated carboxyl groups R can, however, also be carriedout by first converting a compound of the formula I, in which R iscarboxyl, into a reactive derivative in a customary manner, for exampleinto an acid halide by means of a halide or phosphorus or sulphur, forexample by means of phosphorus trichloride or phosphorus tribromide,phosphorus pentachloride or thionyl chloride, or into a reactive ester,i.e. esters having electron-attracting structures, such as the esterswith phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol, or areactive amide, for example the amide derived from imidazole or3,5-dimethylpyrazole, by reaction with a corresponding alcohol or amine,and then reacting the resulting reactive derivative in a customarymanner, for example as described below for the transesterification,trans-amidation and inter-conversion of esterified and amidated carboxylgroups R, with a corresponding alcohol, ammonia or the correspondingamine containing at least one hydrogen atom, to give the desired groupR.

An esterified carboxyl group R can, in a customary manner, be convertedto a free carboxyl group R, for example by hydrolysis in the presence ofa catalyst, for example of a basic or acid agent, such as a strong base,for example sodium hydroxide or potassium hydroxide, or a mineral acid,for example hydrochloric acid, sulphuric acid or phosphoric acid, or toan amidated carboxyl group R, for example by reaction with ammonia orthe corresponding amine containing at least one hydrogen atom.

An esterified carboxyl group R can also be transesterified to anotheresterified carboxyl group R in a customary manner, for example byreaction with a metal salt, such as the sodium or potassium salt, of acorresponding alcohol or with the alcohol itself, in the presence of acatalyst, for example of a strong base, for example sodium hydroxide orpotassium hydroxide, or of a strong acid, such as a mineral acid, forexample hydrochloric acid, sulphuric acid of phosphoric acid, or of anorganic sulphonic acid, for example p-toluenesulphonic acid, or of aLewis acid, for example boron trifluoride etherate.

An amidated carboxyl group R can be converted to the free carboxyl groupR in a customary manner, for example by hydrolysis in the presence of acatalyst, for example of a strong base, such as an alkali metalhydroxide or alkali metal carbonate or an alkaline earth metal hydroxideor alkaline earth metal carbonate, for example sodium hydroxide orsodium carbonate or potassium hydroxide or potassium carbonate, or of astrong acid, such as a mineral acid, for example hydrochloric acid,sulphuric acid or phosphoric acid.

Futhermore, in a compound obtainable according to the invention, free,esterified or etherified hydroxyl groups R₂ can be converted into oneanother.

Thus, for example, a free hydroxyl group R₂ can be esterified to ahydroxyl group R₁ and/or R₂ esterified by a carboxylic acid, by reactionwith a preferably functionally modified carboxylic acid, such as a loweralkanecarboxylic acid, for example acetic acid, or etherified to anetherified hydroxyl group, for example a lower alkoxy group, R₁ and/orR₂, by reaction with an etherifying agent, for example with a loweralkylating agent.

A functionally modified carboxylic acid is, for example, an anhydride,such as the symmetrical anhydrides thereof, or an anhydride with ahydrogen halide acid, such as hydrochloric acid or hydrobromic acid, areactive ester, i.e. an ester having electron-attracting structures, forexample the phenyl, (p-nitro)-phenyl, or cyanomethyl ester of a loweralkanecarboxylic acid, or a reactive amide, for example an N-loweralkanoylimidazole or a N-lower alkanoyl-3,5-dimethylpyrazole.

Etherifying agents are, for example, reactive esterified alcohols, suchas alcohols esterified by a mineral acid, for example by hydriodic acid,hydrochloric acid or hydrobromic acid or sulphuric acid, or an organicsulphonic acid, for example by p-toluenesulphonic acid,p-bromobenzenesulphonic acid, benzenesulphonic acid, methanesulphonicacid, ethanesulphonic acid or ethenesulphonic acid, or fluorosulphonicacid, and also diazoalkanes. Etherifying agents which may be mentionedin particular are lower alkyl chlorides, lower alkyl iodides and loweralkyl bromides, for example methyl iodides, di-lower alkyl sulphates,for example dimethyl sulphate or diethyl sulphate, or methylfluorosulphonate, lower alkyl sulphonates, such as lower alkyl, forexample methyl, p-toluenesulphonate, p-bromobenzenesulphonate,methanesulphonate or ethanesulphonate, and also diazo-alkanes, forexample diazomethane.

The reactions with acids, preferably functionally modified acids, andwith etherifying agents, for example those singled out above, can becarried out in a customary manner, for example in an inert solvent, suchas an ether, for example in tetrahydrofurane, in the case of thereaction with a diazoalkane or, when reactive esterified alcohols areused, for example in the presence of a basic condensing agent, such asof an inorganic base, for example sodium hydroxide or sodium carbonate,potassium hydroxide or potassium carbonate or calcium hydroxide orcalcium carbonate, or of a tertiary or quaternary nitrogen base, forexample pyridine, α-picoline, quinoline or triethylamine, ortetraethyl-ammonium hydroxide or benzyltriethyl-ammonium hydroxide,and/or of a solvent customary for the particular reaction, which solventcan also comprise an excess of the functional acid derivative used forthe esterification, for example of a lower alkanoic acid anhydride oracid chloride, or the lower alkyl halide or lower alkyl sulphate use,for example, for the etherification, and/or a tertiary nitrogen baseused as the basic condensing agent, for example triethylamine orpyridine, if necessary at elevated temperature. Methylation by means ofacyl iodide in amyl alcohol/potassium carbonate at the boiling point andalso acylation by means of a lower alkanoic acid anhydride at 50°-150°or by means of a lower alkanoyl chloride in pyridine orpyridine-triethylamine at temperatures between -20° and +100° C. areespecially to be recommended.

Conversely, etherified or, in particular, esterified hydroxyl R₂ canalso be converted into hydroxyl in a customary manner, for example inthe presence of an acid agent, such as a hydrogen halide acid, forexample hydriodic acid, in an inert solvent, for example in ethanol oracetic acid.

Furthermore, in a compound obtainable according to the invention, acylR₂ and/or, in particular, R₁ can be replaced by hydrogen. Thus, acarboxyl group R₂ and/or, in particular, R₁ can be decarboxylated in acustomary manner, for example by the action of heat, or the acyl groupR₁ of a carboxylic acid can be split off in a customary manner, such asby the action of basic agents, such as alkalis, for example dilutesodium hydroxide solution or, in particular, sodium carbonate solution,preferably about 5% strength sodium carbonate solution.

Depending on the choice of the starting materials and procedures, thenovel compounds can be in the form of one of the possible isomers or inthe form of a mixture thereof, for example in the form of isomers inrespect of the orientation of X, and also, depending on the number ofasymmetrical carbon atoms, in the form of pure optical isomers, such asantipodes, or in the form of mixtures of isomers, such as racemates,mixtures of diasteromers or mixtures of racemates.

Resulting mixtures of isomers in respect of the orientation of X,mixtures of diasteromers and mixtures of racemates can be separated onthe basis of the physical/chemical differences between the constituentsinto the pure isomers, diasteromers or racemates in a known manner, forexample by chromatography and/or fractional crystallisation.

Resulting racemates can also be resolved into the optical antipodes byknown methods, for example by recrystallisation from an optically activesolvent, with the aid of nitro organisms or by reaction of an acid endproduct with an optically active base which forms salts with the racemicacid and separation of the salts obtained in this way, for example onthe basis of their different solubilities, into the diasteromers, fromwhich the antipodes can be set free by the action of suitable agents.Advantageously, the more active of the two antipodes is isolated.

Resulting free compounds of the formula I, for example those in which R,R₁ and/or R₂ is carboxyl, can be converted into salts in a manner whichis known per se, inter alia by treatment with a base or with a suitablesalt of a carboxylic acid, usually in the presence of a solvent ordiluent.

Resulting salts can be converted into the free compounds in a mannerwhich is known per se, for example by treatment with an acid reagent,such as a mineral acid.

The compounds, including their salts, can also be obtained in the formof their hydrates or can incorporate the solvent used forcrystallisation.

Because of the close relationship between the novel compounds in thefree form and in the form of their salts, the free compounds or theirsalts, in the preceding and following text, are, where appropriate, alsoto be understood to include the corresponding salts or free compounds,in respect of general sense and intended use.

The invention also relates to those embodiments of the process in whicha compound obtainable as an intermediate at any stage of the process isused as the starting material and the missing steps are carried out, ora starting material is used in the form of a salt and/or racemate orantipode or, especially, is formed under the reaction conditions.

The starting materials are known or, if they are novel, can be preparedaccording to methods which are known per se.

Thus, the starting materials of the general formula (II) can beprepared, for example, when, in a compound of the formula ##STR10## inwhich Ph and X have the defined meanings and R" is nitro or an acylatedamino group which differs from a group of the formula RCONR₃ --, thenitro group R" is converted by conventional reduction, for examplecatalytically or using a metal and an acid, for example using iron andhydrochloric acid, or sodium hyposulphite in aqueous ammonia, intoprimary amino, or an acylated amino group R" is converted byconventional hydrolysis, preferably in the presence of an acid, such asa mineral acid, for example hydrochloric acid or sulphuric acid, or ofan inorganic base, for example sodium hydroxide solution or potassiumhydroxide solution, into an amino group --NHR₃. Primary amino which isfirst formed can easily be alkylated to --NHR₃, for example using alower alkyl halide.

Starting materials of the general formula (II) can also be prepared whena compound of the general formula ##STR11## is subjected to acondensation reaction with an ester of an acid of the formula R₂ COCHR₁COOH, or a compound of the formula ##STR12## is subjected to acondensation reaction with an anhydride, for example with a carboxylicacid or hydrochloric acid, of an acid of the formula R₂ COOH, R'" in theformulae being hydrogen or a group --NHR₃ or R", hydrogen R'" isreplaced by nitro by conventional nitration, nitro is reduced to aminoand, if necessary, acylamino is hydrolysed to amino and/or amino isalkylated to --NHR₃. The reaction is carried out in a conventionalmanner, for example in the presence of a strongly acid condensing agent,such as a mineral acid, for example sulphuric acid, hydrochloric acid orhydrobromic acid, phosphoric acid or polyphosphoric acid, or of anaprotic acid condensing agent, such as an acid anhydride, for examplephosphorus pentoxide or phosphorus oxychloride, or of a Lewis acid, forexample aluminium trichloride, when starting from compounds IIb, or inthe presence of a basic condensing agent, for example of an alkali metalcarboxylate, such as sodium acetate in excess anhydride, or of potassiumcarbonate in acetone, when starting from compounds of the formula IIc.The compounds of the formula IIa, which have been mentioned above asstarting materials, can also be prepared in an analogous manner.

Most of the compounds of the formula III which have been mentioned asstarting materials are novel. In addition to the fact that they can beused as starting materials for the preparation of compounds of theformula I, some of them show further advantageous properties. Thus,compounds of the formula III in which R' is a free or etherifiedglycoloylamino group, and also related compounds in which R' is anesterified glycoloylamino group show the same pharmacologicalproperties, in an activity of comparable strength, as the correspondingcompounds of the formula I.

The invention accordingly also relates to novel starting materials, inparticular compounds of the formula III in which R' is a group of theformula R_(o) --NR₃ and R_(o) is a free or etherified glycoloyl group ora glycoloyl group esterified by a carboxylic acid, processes for theirpreparation, pharmaceutical formulations containing these compounds andthe use of these formulations as pharmaceuticals or for the preparationof medicaments.

Glycoloyl groups esterified by a carboxylic acid are to be understood asmeaning, for example, glycoloyl groups esterified by an aliphatic oraromatic carboxylic acid, for example corresponding loweralkanoyloxy-acetyl or substituted or unsubstituted benzoyloxy-acetyl.Lower alkanoyloxyacetyl is, for example, acetoxy-, propionyloxy-,butyryloxy-, isobutyryloxy-, valeroyloxy-, caproyloxy- orpivaloyloxyacetyl. Possible substituents of substituted benzoyloxyacetylgroups are, in particular, lower alkyl, such as methyl, lower alkoxy,such as methoxy, and/or halogen, such as chlorine.

Etherified glycoloyl groups are, for example, glycoloyl groupsetherified by a substituted or unsubstituted, aliphatic or araliphaticalcohol, such as corresponding lower alkoxy-acetyl or phenyl-loweralkoxy-acetyl groups. Substituents of lower alkoxy-acetyl are, inparticular, hydroxyl, lower alkoxy and/or di-lower alkyl-amino andsubstituents of phenyl-lower alkoxy-acetyl groups are, for example,lower alkyl, such as methyl, lower alkoxy, such as methoxy, and/orhalogen, such as chlorine. Lower alkoxy preferably has one of themeanings defined initially and phenyl-lower alkoxy-acetyl is especiallybenzyloxyacetyl or 2-phenylethoxyacetyl. Di-lower alkyl-amino-loweralkoxyacetyl is preferably 2-dimethyl- or 2-diethyl-aminoethoxyacetyl.

The invention relates especially to those compounds of the formula IIIin which Ph and R₁ have the meanings defined for the particularpreferred catagories of the formula I, R' is a group R_(o) --NR₃ andR_(o) is lower alkoxy-acetyl, in particular having up to 6 carbon atoms,such as methoxyacetyl or ethoxyacetyl, or, preferably, glycoloyl.

The compounds of the formula III, which have been mentioned as startingmaterials, can be prepared by methods which are known per se, preferablyby reacting a compound of the formula ##STR13## or an acid addition saltthereof, with a corresponding acid, for example of the formula X₁ --OH(IIIa), X₂ --OH (IIIb) or R_(o) --OH (IIIc), or a functional derivativethereof, and, if desired, converting a compound which is thus obtainableinto another compound of the formula III in which R' is a group R_(o)--NHR₃.

Functional derivatives of acids of the formula IIIa to IIIc are, inparticular, acid derivatives which contain an esterified or amidatedcarboxyl group or a carboxyl group in the form of an anhydride, such aslower alkoxy-carbonyl, substituted or unsubstituted carbamyl, forexample carbamyl or imidazolyl-1-carbonyl, or halogenocarbonyl, forexample chlorocarbonyl or bromocarbonyl. Examples which may be mentionedin particular of acids of the formula IIIa to IIIc and functionalderivatives thereof are: oxalyl halides, such as oxalyl chloride oroxalyl bromide as functional derivatives of acids of the formula IIIa,as acids of the formulae IIIb and IIIc and functional derivativesthereof, glycollic acid and its lower alkyl esters and the correspondinglactide, or lower alkyl mono-lower alkoxy-acetates, such as ethylmono-lower alkoxy-acetates, for example ethyl ethoxyacetate or ethyldiethoxyacetate, and for the preparation of precursors of compounds ofthe formula III in which R' is a group X₂ --NR₃ -- and X₂ denotesglyoxyloyl, lower alkyl di-lower alkoxyacetates, halogenoaceticanhydrides, such as chloroacetic anhydride or chloroacetyl chloride andtartaric acid, or 2,3-diacetoxysuccinic anhydride, and also cinnamoylchloride, acetyl chloride and glycine.

The reaction of compounds of the formula II with the above-mentionedacids and derivatives thereof can be carried out in a conventionalmanner, for example in the presence of a water-binding agent, such as anacid anhydride, for example phosphorous pentoxide, ordicyclohexylcarbodiimide, or of a condensing agent, for example an acidor basic condensing agent, such as a mineral acid, for examplehydrochloric acid, or an alkali metal hydroxide or alkali metalcarbonate, for example sodium hydroxide or potassium hydroxide, or of anorganic nitrogen base, for example triethylamine or pyridine. In thecase of the reaction with an acid anhydride, such as an acid chloride,an organic nitrogen base is preferably used as the condensing agent. Thereaction with carboxylic acids is preferably carried out in the presenceof a water-binding agent. If necessary, the reaction is in each casecarried out in an inert solvent, at normal temperature or with coolingor warming, for example in the temperature range from about 0° C. toabout 100° C., in a closed vessel and/or under an inert gas, for examplenitrogen.

Compounds of the formula III in which R' is a group --NHR₃ --X₂ and X₂is glyoxyloyl can also be prepared when a corresponding halogeno acetylcompound, such as a bromoacetyl compound, is heated withhexamethylenetetramine, preferably in an aqueous alcohol, or is oxidisedwith silver tetrafluoborate in dimethylsulphoxide. Analogously, achloroacetyl compound can also be oxidised with potassium dichromate inhexamethylphosphoric acid triamide in the presence ofdicyclohexyl-18-crown-6-ether. Compounds of the formula III in which R'is a group X₂ --NHR₃ -- and X₂ is an iminoacetyl group, for examplesubstituted or unsubstituted benzyliminoacetyl, can be prepared startingfrom the corresponding glycyl compounds by reacting these with thecorresponding carbonyl compound, for example with benzaldehyde, andrearranging the intermediate which is thus obtainable, for example abenzylideneglycyl compound, preferably under the reaction conditions.The compounds, according to the invention, of the formula III in whichR' is a group of the formula R_(o) --NHR₃ -- and R_(o) is a free oretherified glycoloyl group or a glycoloyl group esterified by acarboxylic acid can also be prepared by converting the radical R' in acompound of the formula III, in which R' is a radical which can beconverted into the group R_(o) NHR₃ --, into the desired group R_(o)--NHR₃ -- and, if desired, converting a compound which is thusobtainable into another compound of the formula III in which R' is agroup R_(o) NHR₃ --.

Radicals which can be converted into a group R_(o) --NHR₃ -- are thoseof the formula X₁ '--NHR₃ --, in which X₁ ' is an esterified glycoloylgroup which differs from a glycoloyl group which can be free oresterified by a carboxylic acid, for example a glycoloyl groupesterified by a mineral acid, for example by a hydrogen halide acid,such as chloroacetyl or bromoacetyl. Groups X₁ ' of this type can beconverted to a glycoloyl group by hydrolysis, for example in thepresence of a basic hydrolysing agent, such as sodium hydroxidesolution, or into etherified glycoloyl groups or glycoloyl groupsesterified by a carboxylic acid by reaction with a salt, such as analkali metal salt, for example the sodium salt, of a correspondingalcohol or, respectively, of a corresponding carboxylic acid.

Further radicals R' which can be converted into groups of the formulaR_(o) --NHR₃ -- are those of the formula X₂ '--NHR₃ --, in which X₂ ' isa radical which can be converted by reduction into the glycoloyl group,such as the glyoxyloyl group, which can be in the form of a hydrate.This group can also be formed under the reduction conditions from anoxalo group, for example from an oxalo group in the free form or in theform of a salt, such as in the form of the sodium salt, or in the formof an anhydride or ester, such as halogenooxalyl, for examplechlorooxalyl or bromooxalyl, or a mixed anhydride withdiphenylphosphoric acid, or in the form of a lower alkyl ester, forexample in the form of the methyl or isopropyl ester. The reduction ofsuch groups is effected in a conventional manner. Starting fromhalogenooxalyl, catalytically activated hydrogen, for example hydrogencatalytically activated by palladium on a support, such as bariumsulphate, if necessary in the presence of a sulphur-containingco-catalyst, such as thiourea, is preferably used. Anhydrides withdiphenylphosphoric acid are advantageously reduced with an excess ofsodium boronate. Oxalo groups in the form of a salt are advantageouslyreduced with a borane, such as diborane or a borane/ether complex, forexample with borane in tetrahydrofurane, whilst oxalo groups in the formof an ester are advantageously reduced with sodium anilino-borohydride,which is obtainable by the reaction of sodium borohydride andacetanilide in pyridine.

A compound, according to the invention, of the formula III which is thusobtainable can be converted into another compound, according to theinvention, of the formula III.

Thus, for example, the inter-conversions of free, esterified oretherified hydroxyl groups R₂ and the separation of isomers in respectof the orientation of X can be applied to the compounds according to theinvention.

Furthermore, glycoloyl groups R_(o) can be esterified by reaction withan esterifying agent, such as a corresponding carboxylic acid anhydride,for example a lower alkanoic acid anhydride or acid chloride,advantageously in the presence of a base, such as triethylamine orpyridine. Glycoloyl groups R_(o) can also be etherified, for example byconversion into an alkali metal salt, such as the sodium salt, andreaction with a reactive derivative of the particular alcohol, such as alower alkyl halide, for example a lower alkyl bromide, or a di-loweralkyl sulphate. Furthermore, glycoloyl groups R_(o) esterified by acarboxylic acid can be hydrolysed to glycoloyl, for example in thepresence of a hydrolysing agent, such as a base, such as sodiumhydroxide solution.

In the process of the present invention, the starting materials used arepreferably those which lead to the compounds described initially asbeing particularly valuable.

The present invention also relates to pharmaceutical formulations whichcontain one of the compounds, according to the invention, of the formulaI or III or a salt thereof which can be used pharmaceutically. Thepharmaceutical formulations according to the invention are those whichare intended for topical and local application and for enteral, such asoral or rectal, and parenteral administration to, and for inhalation by,warm-blooded animals and contain the pharmacological active compound onits own or together with an excipient which can be usedpharmaceutically. The dosage of the active compound depends on thespecies of warm-blooded animal, the age and the state of health of theindividual and also on the mode of administration.

The novel pharmaceutical formulations contain, for example, from about10% to about 95%, and preferably from about 20% to about 90%, of theactive compound. Pharmaceutical formulations according to the inventionare, for example, those in the form of an aerosol or spray or in dosageunit forms, such as dragees, tablets, capsules or suppositories, andalso ampoules.

The pharmaceutical formulations of the present invention are prepared ina manner which is known per se, for example by means of conventionalmixing, granulating, dragee-making, dissolving or lyophilisingprocesses. Thus, pharmaceutical formulations for oral use can beobtained by combining the active compound with solid excipients,granulating a resulting mixture if desired and processing the mixture orgranules, after adding suitable auxiliaries if desired or necessary, togive tablets or dragee cores.

Suitable excipients are, especially, fillers, such as sugars, forexample lactose, sucrose, mannitol or sorbitol, cellulose formulationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders, such as starch pastes using, forexample, maize starch, wheat starch, rice starch or potato starch,gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone,and/or, if desired, disintegrating agents, such as the above-mentionedstarches, and also carboxymethyl-starch, crosslinkedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such assodium alginate. Auxiliaries are, in particular, flow-regulating agentsand lubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium stearate or calcium stearate, and/or polyethyleneglycol. Dragee cores are provided with suitable coatings, which, ifdesired, are resistant to gastric juices, and for this purpose, interalia, concentrated sugar solutions, which can contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or solvent mixtures or,in order to produce coatings resistant to gastric juices, solutions ofsuitable cellulose formulations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate, are used. Dyestuffs or pigmentscan be added to the tablets or dragee coatings, for example foridentification or in order to characterize different doses of the activecompound.

Other pharmaceutical formulations whch can be used orally are push-fitcapsules made of gelatine, as well as soft, sealed capsules made ofgelatine and a plasticiser, such as glycerol or sorbitol. The push-fitcapsules can contain the active compound in the form of granules, forexample mixed with fillers, such as lactose, binders, such as starches,and/or lubricants, such as talc or magnesium stearate, and can containstabilisers. In soft capsules, the active compound is preferablydissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin or liquid polyethylene glycols, it also being possible to addstabilisers.

Possible pharmaceutical formulations which can be used rectally are, forexample, suppositories, which consist of a combination of the activecompound with a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols. In addition it is also possibleto use gelatine rectal capsules which contain a combination of theactive compound with a base; bases which can be used are, for example,liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Formulations suitable for parenteral administration are, in particular,aqueous solutions of an active compound in the water-soluble form, forexample of a water-soluble salt, and also suspensions of the activecompound, such as corresponding oily injection suspensions, in whichcase suitable lipophilic solvents or vehicles, such as fatty oils, forexample sesame oil, or synthetic fatty acid esters, for example ethyloleate or triglycerides, are used, or aqueous injection suspensionswhich contain substances which increase the viscosity, for examplesodium carboxymethylcellulose, sorbitol and/or dextran, and can alsocontain stabilisers.

Inhalation formulations for the treatment of the respiratory passages bynasal or buccal administration are, for example, aerosols or sprayswhich can disperse the pharmacological active compound in the form of apowder or in the form of drops of a solution or suspension. Formulationswhich have powder-dispersing properties usually contain, in addition tothe active compound, a liquid propellant gas which has a boiling pointbelow room temperature and also, if desired, excipients, such as liquidor solid non-ionic or anionic surface-active agents and/or soliddiluents. Formulations in which the pharmacological active compound isin solution contain, in addition to this active compound, a suitablepropellant and also, if necessary, an additional solvent and/or astabiliser. In place of the propellant gas, it is also possible to usecompressed air and this can be produced as required by means of asuitable compression and pressure release device.

Pharmaceutical formulations for topical and local use are, for example,lotions and creams which contain a liquid or semi-solid oil-in-water orwater-in-oil emulsion, and ointments (such formulations preferablycontaining a preservative) for the treatment of the skin, eyedrops whichcontain the active compound in aqueous or oil solution and eyeointments, which are preferably prepared in a sterile form, for thetreatment of the eyes, powders, aerosols and sprays (similar to thosedescribed above for the treatment of the respiratory passages) and alsocoarse powders, which are administered through the nostrils by rapidinhalation, and nosedrops, which contain the active compound in aqueousor oily solution, for the treatment of the nose, or lozenges, whichcontain the active compound in a composition generally consisting ofsugar and gum arabic or tragacanth, to which flavourings can be added,as well as pastilles, which contain the active compound in an inertcomposition, for example consisting of gelatine and glycerol or sugarand gum arabic, for the local treatment of the mouth.

The invention also relates to the use of the novel compounds of theformula (I) and salts thereof, as pharmacologically active compounds andespecially as anti-allergic agents, preferably in the form ofpharmaceutical formulations. The daily dose which is administered to awarm-blooded animal weighing about 70 kg is from about 200 mg to about1,200 mg.

The examples which follow illustrate the invention described above;however, they are not intended to restrict the scope of the invention inany way. Temperatures are given in degrees centrigrade.

EXAMPLE 1

35 g of 7-amino-4-methyl-coumarin and 24.5 g of triethylamine areinitially introduced into 400 ml of dimethylformamide. A solution of29.5 g of oxalic acid monomethyl ester-chloride in 100 ml ofdimethylformamide is added dropwise to this mixture in the course of 15minutes. The reaction temperature is kept below 35° by external cooling.The yellow, thick suspension is stirred overnight at room temperatureand then poured into 2 liters of ice-water. The suspension is filteredwith suction and the precipitate is recrystallised from acetone. Thisgives 7-methoxyoxalylamino-4-methyl-coumarin with a melting point of248°-51°.

EXAMPLE 2

13.2 g of 7-amino-4,6-dimethyl-coumarin and 7 g of triethylamine areinitially introduced into 250 ml of dimethylformamide and the mixture iswarmed to 45°. Virtually everything goes into solution. 9.5 g of oxalicacid monomethyl ester-chloride in 100 ml of dimethylformamide are nowadded dropwise. The internal temperatue is kept below 45° by externalcooling. Everything goes into solution at the start of the dropwiseaddition and a slight precipitate then separates out. The resultingsuspension is stirred overnight at room temperature. Thedimethylformamide is stripped off in vacuo and the residue is dilutedwith water and extracted by shaking with chloroform. The chloroformphase is separated off, washed with water, dried over anhydrous sodiumsulphate and evaporated to dryness in vacuo. This gives crude4,6-dimethyl-7-methoxyoxalyl-amino-coumarin which, afterrecrystallisation from chloroform, melts at 222°-5°.

EXAMPLE 3

3 g of 7-methoxyoxalylamino-4-methyl-coumarin are suspended in 50 ml ofN sodium hydroxide solution and the suspension is stirred for 21/2 hoursat 30°-35°. A clear solution is obtained and this is acidified withdilute hydrochloric acid. The precipitate formed is filtered off withsuction and recrystallized from acetone. This gives 2.6 g of4-methyl-7-oxaloamino-coumarin with a melting point of 236°-38°(decomposition). The sodium salt melts above 300°.

EXAMPLE 4

The following compounds can also be prepared in a manner analogous tothat described in Examples 1 to 3:8-methoxyoxalylamino-4-methyl-coumarin,7-methoxyoxalylamino-3-phenyl-coumarin, melting point 250°-252°,7-methoxyoxalylamino-3-(3-pyridyl)-coumarin,4-hydroxy-7-methoxyoxalylamino-coumarin,6-methoxy-7-methoxyoxalylamino-coumarin, 6-methoxyoxalylamino-coumarin,6-methoxyoxalylamino-4-methyl-coumarin,3-acetyl-7-methoxyoxalylamino-coumarin,3,4-dimethyl-7-methoxyoxalylamino-coumarin, melting point 258°-260°,2,3-dimethyl-6-methoxyoxalylamino-chromone,7-methoxyoxalylamino-3-methyl-flavone,6-chloro-8-methoxyoxalylamino-4-methyl-coumarin,4,6-dimethyl-8-methoxyoxalylamino-coumarin,4,5-dimethyl-8-methoxyoxalylamino-coumarin,3-acetyl-4-hydroxy-7-methoxyoxalyl-amino-coumarin, melting point205°-206°, 6-methoxy-5-methoxyoxalyl-amino-coumarin and4-methyl-7-(4-methyl-7-cumaryl)-aminooxalyl-amino-coumarin.

EXAMPLE 5

The following compounds can also be prepared in a manner analogous tothat described in Examples 1 to 3:7-ethoxyoxalylamino-4-methyl-coumarin, with a melting point of218°-220°, starting from 8.7 g of 7-amino-4-methyl-coumarin and3,4-dimethyl-7-oxaloamino-coumarin, with a melting point of 233°,starting from 5.5 g of 3,4-dimethyl-7-methoxyoxalylamino-coumarin.

EXAMPLE 6

10.5 g of 7-amino-4-methyl-coumarin are dissolved in 6 g oftriethylamine and 70 ml of dimethylformamide and the solution is treateddropwise with 3.8 g of oxalyl chloride, with external cooling and whilestirring. The mixture is stirred overnight at room temperature andpoured into ice water, the resulting mixture is acidified to pH 5 to 6with 2 N hydrochloric acid and the precipitate is filtered off withsuction. The crystalline material is suspended in ethanol, thesuspension is digested warm and the precipitate is filtered off withsuction. This gives4-methyl-7-(4-methyl-7-cumaryl)-aminooxalylamino-coumarin. This productis again digested with dimethylformamide and again filtered off withsuction. It melts above 300°.

EXAMPLE 7

7-Methoxyoxalylamino-3-phenyl-coumarin with a melting point of 250°-252°can be prepared in a manner analogous to that described in Examples 1and 2, starting from 6 g of 7-amino-3-phenyl-coumarin.

The starting material can be prepared as follows: 40 g of2-methoxy-4-acetyl-amino-benzaldehyde and 223.2 g of benzyl cyanide aredissolved in 525 ml of ethanol, with warming. A mixture of 19.7 ml of50% strength potassium hydroxide solution and 105 ml of ethanol is thenadded dropwise at 30°-35°. After stirring for 30 minutes at 40°-45°, themixture is left to stand overnight. The reaction solution is thendiluted with water, the ethanol is stripped off in vacuo and the aqueousphase is extracted thoroughly with ether. The dried ether solution isevaporated to dryness in vacuo and the residual oil is distilled under0.1 mm Hg. α-Phenyl-2-methoxy-4-acetylamino-cinnamonitrile passes overat 62°. 63 g of α-phenyl-2-methoxy-4-acetylamino-cinnamonitrile aredissolved in 500 ml of warm toluene. A little nitrile precipitates againon cooling to 50°. 150 g of aluminium chloride are then added in 6portions, and the internal temperature rises to 68°. The dark greenmixture is kept at 80° for 6 hours. It is then poured on to a mixture of800 g of ice and 100 ml of concentrated hydrochloric acid, the tolueneis stripped off in vacuo and the product which has precipitated isfiltered off with suction, 700 ml of 85% strength acetic acid and 120 mlof concentrated hydrochloric acid are poured over the product and themixture is heated under reflux overnight. After cooling, crystalline7-amino-3-phenyl-coumarin, which has separated out, is filtered off withsuction and recrystallised from ethanol/ethyl acetate. It melts at205°-208°.

EXAMPLE 8

N-Ethyl-7-methoxyoxalylamino-4-methyl-coumarin with a melting point of136°-8° can be prepared in a manner analogous to that described inExamples 1 and 2, starting from 25.2 g of7-ethylamino-4-methyl-coumarin.

7-Ethylamino-4-methyl-coumarin, which is used as the starting material,is obtained from 50 g of 3-ethylaminophenol by heating this with 55.5 gof ethyl acetoacetate and 39.7 g of zinc chloride in 190 ml of ethanolfor 12 hours under reflux. For working up, the reaction mixture ispoured into 3,000 ml of water, the resulting mixture is stirred for 2hours and 7-ethylamino-4-methyl-coumarin is filtered off with suction.After recrystallisation from ethanol, it melts at 154°-155°.

EXAMPLE 9

N-Ethyl-7-oxaloamino-4-methyl-coumarin with a melting point of 142° isobtained in a manner analogous to that described in Example 3, startingfrom 14 g of N-ethyl-7-methoxyoxalylamino-4-methyl-coumarin.

EXAMPLE 10

N-Methyl-7-methoxyoxalylamino-4-methyl-coumarin with a melting point of164°-165° is obtained in a manner analogous to that described inExamples 1 and 2, starting from 10.6 g of7-methylamino-4-methylcoumarin.

The starting material is prepared from 67.4 g of 3-methylamino-phenol ina manner analogous to that described in Example 7 for7-ethyl-amino-4-methyl-coumarin. 7-Methylamino-4-methyl-coumarin meltsat 193°-4°.

EXAMPLE 11

N-Methyl-7-oxaloamino-4-methyl-coumarin with a melting point of 162°-64°is obtained in a manner analogous to that described in Example 3,starting from 13.5 g of N-methyl-7-methoxyoxalylamino-4-methyl-coumarin.

EXAMPLE 12

8-Methoxyoxalylamino-7-methoxy-4-methyl-coumarin with a melting point of228°-29° can be prepared in a manner analogous to that described inExamples 1 and 2, starting from 9.7 g of8-amino-7-methoxy-4-methyl-coumarin.

The starting material can be prepared as follows:

A mixture of 16.3 ml of 65% strength nitric acid and 17 ml ofconcentrated sulphuric acid is added slowly dropwise to a solution of45.5 g of β-methylumbelliferone in 100 ml of concentrated sulphuric acidwith external cooling (internal temperature below 5°). After thedropwise addition has ended, the ice bath is removed and the mixture isstirred further at room temperature. As soon as the internal temperaturehas reached 20°, the mixture is poured into 1,200 ml of ice water andthe product which has separated out is filtered off with suction. Amixture of 6-nitro- and 8-nitro-β-methylumbelliferone with a meltingpoint of 223°-229° is obtained. This mixture is heated in acetone with123.9 g of methyl iodide in the presence of 139.6 g of potassiumcarbonate for 19 hours under reflux. The acetone is stripped off invacuo and the evaporated residue is treated with 400 ml of water. Thematerial which has not dissolved is filtered off with suction. Thisgives 8-nitro-7-methoxy 4-methyl-coumarin with a melting point of 233°.6-Nitro-β-methylumbelliferone with a melting point of 243° can beisolated, as the single product, from the filtrate by acidifying withconcentrated acid.

8-Amino-7-methoxy-4-methyl-coumarin with a melting point of 152°-155° isobtained from 8-nitro-7-methoxy-4-methyl-coumarin by reducing the nitrogroup with sodium hyposulphite.

EXAMPLE 13

The following compounds can also be prepared in a manner analogous tothat described in Examples 1 to 3:8-oxaloamino-7-methoxy-4-methyl-coumarin starting from8-methoxyoxalylamino-7-methoxy-4-methyl-coumarin,6-methoxyoxalylamino-7-hydroxy-4-methyl-coumarin starting from6-amino-β-methylumbelliferone (obtainable by reduction of the nitrogroup) and 6-oxaloamino-7-hydroxy-4-methyl-coumarin starting from6-methoxyoxalylamino-7-hydroxy-4-methyl-coumarin.

EXAMPLE 14

4,6-Dimethyl-7-oxaloamino-coumarin, melting point 250°-251°(decomposition), 7-methoxyoxalylamino-3,4-tetramethylene-coumarin,melting point 231°-232°, and 7-oxaloamino-3,4-tetramethylene-coumarinmonohydrate, melting point 235° (decomposition), can also be prepared ina manner analogous to that described in Examples 1 to 3.

EXAMPLE 15

2,3-Dimethyl-6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane with a meltingpoint of 242°-244° can be obtained in a manner analogous to thatdescribed in Examples 1 to 3, starting from 12 g of2,3-dimethyl-6-amino-4-oxo-4H-1-benzopyrane.

The starting material can be prepared as follows:

150 g of phosphorus pentoxide are added to 100 g of ethyl2-methylacetoacetate and 100 g of phenol in 300 ml of toluene, whilestirring. After briefly warming to 40°, an exothermic reaction startsand the internal temperature rises up to 40°. The mixture is then warmedat an internal temperature of about 100° for 2 hours, cooled somewhat(about 80°) and, after adding a further 100 g of phenol and 100 g ofphosphorus pentoxide, again heated at 100° for 2 hours. The reactionmixture is diluted with 300 ml of toluene and poured, while still hot,into 1,500 ml of ice-water. The resulting mixture is rendered alkalinewith concentrated sodium hydroxide solution and saturated with sodiumchloride. It is then stirred vigorously for 45 minutes and the organicphase is separated off, washed with 400 ml of 2 N sodium hydroxidesolution and then with 600 ml of a saturated solution of sodiumchloride, dried and evaporated to dryness. The residual oil is subjectedto fractional distillation in vacuo and the fractions which pass over at170°/13 mm are collected and crystallized from isopropanol/petroleumether. The resulting 2,3-dimethyl-4-oxo-4H-1-benzopyrane with a meltingpoint of 91°-3° is nitrated in 70 ml of concentrated sulphuric acid atbelow 5° with 6.9 ml of fuming nitric acid and6-nitro-2,3-dimethyl-4-oxo-4H-1-benzopyrane, which is thus obtainable,is reduced, in dimethylformamide, with hydrogen in the presence of Raneynickel. 6-Amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane, which is thusobtained, melts at 202°-204°.

EXAMPLE 16

7.4 g of 2,3-dimethyl-6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane arewarmed for 5 minutes at 70° with 26.9 ml of N sodium hydroxide solutionin 100 ml of water. A solution forms. After stirring for 90 minutes atroom temperature, the crystalline sodium salt of2,3-dimethyl-6-oxaloamino-4-oxo-4H-1-benzopyrane, which has separatedout and has a melting point about 265°, is filtered off.

EXAMPLE 17

7-Methoxyoxalylamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane with a meltingpoint of 228°-29° can be prepared in a manner analogous to thatdescribed in Example 1 and 2, starting from 17.2 g of7-amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane.

The starting material can be prepared as follows:

30 g of 2-hydroxy-4-acetylamino-propiophenone are heated with 14.3 g ofanhydrous sodium acetate in 25.5 ml of acetic anhydride for 6 hoursunder reflux, the warm suspension is poured into ice-water, theresulting mixture is stirred for 30 minutes and the precipitate isfiltered off with suction.7-Acetylamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane melts at 259°-61°.Saponification to give 7-amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane(melting point 224°-26°) is effected by boiling under reflux inconcentrated hydrochloric acid for 90 minutes.

EXAMPLE 18

7-Oxaloamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane with a melting point of234°-40° can be obtained in a manner analogous to that described inExample 3, starting from 9 g of7-methoxyoxalylamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane.

EXAMPLE 19

7-Methoxyoxalylamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with amelting point of 239° is obtained in a manner analogous to thatdescribed in Example 1 and 2, starting from 11 g of7-amino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane.

The starting material can be prepared as follows:

35 g of 2-hydroxy-4-acetylaminopropiophenone, 23.8 g of benzoyl chlorideand 169.1 g of potassium carbonate are heated in 3,800 ml of acetone for8 hours under reflux. The acetone is stripped off in vacuo and theresidue is treated with 1,200 ml of water. The resulting mixture isstirred well and the material which has not dissolved is filtered offwith suction, washed successively with 5% strength sodium hydroxidesolution and water and dried in vacuo. The resulting material is thenheated with 420 ml of saturated methanolic hydrochloric acid for 1 hourunder reflux. The methanol is distilled off in vacuo and the residue istreated with concentrated ammonia solution. The product which separatesout is filtered off with suction and digested with toluene and7-amino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with a melting point of204°-206°, which remains undissolved, is filtered off.

7-Oxaloamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with a meltingpoint of 243° can be obtained in a manner analogous to that described inExample 3, starting from 7.5 g of7-methoxyoxalylamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane.

EXAMPLE 20

1 g of 7-hydroxyacetamido-4-methyl-coumarin is dissolved in 60 ml ofacetone and the solution is stirred with 1 g of potassium permanganatein 50 ml of water for 40 hours at room temperature.7-Oxalo-amino-4-methylcoumarin is extracted with 2 N sodium hydroxidesolution and precipitated by acidifying. It melts at 236°-238° withdecomposition.

The starting material can be prepared as follows:

8.7 g of 7-amino-4-methyl-coumarin are stirred, under nitrogen, in around-bottomed flask, together with 7.6 g of glycollic acid at an oilbath temperature of 150°-160°. The reaction mass becomes crystallineafter about 30 minutes. It is diluted with water and the product isfiltered off with suction and recrystallised from 200 ml ofdimethylformamide and 100 ml of ethanol.7-Hydroxyacetamido-4-methyl-coumarin with a melting point of 253°-254°is obtained.

EXAMPLE 21

The following compounds can also be prepared in a manner analogous tothat described in Examples 1 to 20:6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane,6-oxaloamino-4-oxo-4H-1-benzopyrane,6-methoxyoxalylamino-2-methyl-4-oxo-4H-1-benzopyrane,6-oxaloamino-2-methyl-4-oxo-4H-1-benzopyrane,6-oxaloamino-3-(2-pyridyl)-coumarin,8-methoxyoxalylamino-3-(2-pyridyl)-coumarin,8-oxaloamino-3-(2-pyridyl)-coumarin, 6-methoxy-5-oxaloamino-coumarin,8-methoxyoxalylamino-coumarin, 8-oxaloamino-coumarin,5-methoxyoxalylamino-coumarin, 5-oxaloaminocoumarin-coumarin,6-methoxy-5-methoxyoxalylamino-4-methyl-coumarin,6-methoxy-4-methyl-5-oxaloamino-coumarin,6-hydroxy-4-methyl-5-oxaloamino-coumarin,6-hydroxy-4-methyl-5-oxaloamino-coumarin,7-methoxy-4-methyl-8-oxaloamino-coumarin, melting point 214° and7-methoxy-8-methoxyoxalylamino-4-methyl-coumarin, melting point 216°.7-Methoxyoxalylaminocoumarin, 6-oxaloaminocoumarin,7-oxaloaminocoumarin, 4-methyl-6-oxaloamino-coumarin,4-hydroxy-6-methoxyoxalylaminocoumarin,6-methoxyoxalylamino-3-(2-pyridyl)-coumarin, melting point 240°-242°(decomposition) and 4-hydroxy-6-oxaloaminocoumarin.

EXAMPLE 22

Tablets containing 0.1 g of 7-oxaloamino-4-methylcoumarin are preparedas follows:

    ______________________________________                                        Composition (for 1,000 tablets):                                              ______________________________________                                        7-Oxaloamino-4-methyl-coumarin                                                                          100 g                                               Lactose                   50 g                                                Wheat starch              73 g                                                Colloidal silica          13 g                                                Magnesium stearate        2 g                                                 Talc                      12 g                                                Water                     q.s.                                                ______________________________________                                    

The 7-oxaloamino-4-methyl-coumarin is mixed with a portion of the wheatstarch and with the lactose and the colloidal silica and the mixture isforced through a sieve. A further portion of the wheat starch is mixedto a paste with five times the amount of water on a water bath and theabove pulverulent mixture is kneaded with this paste until a slightlyplastic mass has formed. The plastic mass is passed through a sieve ofabout 3 mm mesh width and dried and the dry granules are again forcedthrough a sieve. The remainder of the wheat starch, the talc and themagnesium stearate are then mixed in and the resulting mixture ispressed to give tablets weighing 0.25 g (with a breaking groove).

Tablets containing, in each case, 100 mg of one of the compounds, of thegeneral formula I, mentioned in Examples 1 and 2 can also be prepared inan analogous manner.

EXAMPLE 23

An approximately 2% strength aqueous solution, which is suitable forinhalation, of a water-soluble active compound according to theinvention, in the free form or in the form of the sodium salt, can, forexample, be prepared in the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        Active compound, for example 4-methyl-                                        7-oxaloamino-coumarin 2,000 mg                                                Stabiliser, for example the disodium salt                                     of ethylenediaminetetraacetic acid                                                                  10 mg                                                   Preservative, for example benzalkonium                                        chloride              10 mg                                                   Freshly distilled water                                                                             to make up to 100 ml                                    ______________________________________                                    

Preparation

The active compound is dissolved in freshly distilled water with theaddition of the equimolecular amount of 2 N sodium hydroxide solution.The stabiliser and the preservative are then added. After all of thecomponents have dissolved completely, the resulting solution is made upto 100 ml and filled into small bottles and these are sealed gas-tight.

2% strength inhalation solutions containing, as the active compound, acompound which is the object of the preparation in one of Examples 1, 2and 4 can also be prepared in an analogous manner.

EXAMPLE 24

An approximately 2% strength aqueous solution, which is suitable forinhalation, of a water-soluble active compound according to theinvention, in the free form or in the form of the sodium salt, can, forexample, be prepared in the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        Active compound, for example the sodium                                       salt of 3,4-dimethyl-7-oxaloamino-                                            coumarin              2,000 mg                                                Stabiliser, for example the disodium salt                                     of ethylenediaminetetraacetic acid                                                                  10 mg                                                   Preservative, for example benzalkonium                                        chloride              10 mg                                                   Freshly distilled water                                                                             to make up to 100 ml                                    ______________________________________                                    

Preparation

The active compound is dissolved in freshly distilled water. Thestabiliser and the preservative are then added. After all of thecomponents have dissolved completely, the resulting solution is made upto 100 ml and filled into small bottles and these are sealed gas-tight.

2% strength inhalation solutions containing, as the desired compound,another compound which is the object of the preparation in one ofExamples 5 to 21 can also be prepared in an analogous manner.

EXAMPLE 25

Capsules suitable for insufflation and containing about 25 mg of anactive compound according to the invention can, for example, be preparedin the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        Active compound, for example 7-methoxyoxalyl-                                 amino-4-methyl-coumarin    25 g                                               Very finely ground lactose 25 g                                               ______________________________________                                    

Preparation

The active compound and the lactose are intimately mixed. The resultingpowder is then sieved and filled in 50 mg portions into 1,000 gelatinecapsules.

Insufflation capsules containing, in each case, a compound which is theobject of the preparation according to one of Examples 2 to 4 can alsobe prepared in an analogous manner.

EXAMPLE 26

Capsules suitable for insufflation and containing about 25 mg of anactive compound according to the invention can, for example, be preparedin the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        Active compound, for example 3,4-dimethyl-7-                                  oxaloamino-coumarin       25 g                                                Very finely ground lactose                                                                              25 g                                                ______________________________________                                    

Preparation

The active compound and the lactose are intimately mixed. The resultingpowder is then sieved and filled in 50 mg portions into 1,000 gelatinecapsules.

Insufflation capsules containing, in each case, another compound whichis the object of the preparation according to one of Examples 5 to 19can also be prepared in an analogous manner.

I claim:
 1. A benzopyrane compound having the formula ##STR14## in whichR_(o) is glycoloyl or lower alkoxy-acetyl having up to 6 carbon atoms,Ph' is 1,2-phenylene which contains the group R_(o) --NH-- and, inaddition, is otherwise unsubstituted or is additionally substituted bylower alkyl, lower alkoxy, halogen, hydroxyl and trifluoromethyl, R₁ 'and R₂ ' conjointly are tri-, tetra- or penta-methylene, or R₁ ' ishydrogen, lower alkanoyl, carboxyl, lower alkoxy-carbonyl, lower alkyl,or phenyl or pyridyl which are unsubstituted or substituted by loweralkyl, lower alkoxy, halogen, hydroxyl and trifluoromethyl, and R₂ ' hasone of the meanings given for R₁ ' or is hydroxyl, lower alkoxy, orlower alkanoyloxy, or a pharmaceutically acceptable salt thereof.
 2. Abenzopyrane compound as claimed in claim 1, having the formula ##STR15##in which R_(o) is glycoloyl or lower alkoxy-acetyl having up to 6 carbonatoms, Ph' is 1,2-phenylene which contains the group R_(o) --NH--, andis otherwise unsubstituted or substituted in one of the free positionsby lower alkyl or lower alkoxy having, in each case, up to 4 C atoms, orhydroxyl or halogen, R₁ ' is hydrogen or lower alkyl or lower alkanoyl,having, in each case, up to 4 C atoms, or is phenyl or pyridyl and R₂ 'has one of the meanings given for R₁ ' or is hydroxyl or lower alkoxyhaving up to 4 C atoms, or a pharmaceutically acceptable salt thereof.3. A benzopyrane compound as claimed in claim 1, having the formula##STR16## in which one of the radicals R₆ and R₇ is a group of theformula R_(o) --NH--, in which R_(o) is glycoloyl, and the other ishydrogen and R₃ and R₄ independently of one another are hydrogen orlower alkyl having up to 4 C atoms, or a pharmaceutically acceptablesalt thereof.
 4. A compound as claimed in claim 1 and being7-hydroxyacetamido-4-methyl-coumarin.